Effect of rosiglitazone on peroxisome proliferator-activated receptor gamma gene expression in human adipose tissue is limited by antiretroviral drug-induced mitochondrial dysfunction.
BACKGROUND
Treatment of human immunodeficiency virus (HIV)-1 with thymidine-analogue nucleoside reverse-transcriptase inhibitors (tNRTIs) causes lipoatrophy, mitochondrial toxicity, and lower adipose tissue expression of peroxisome proliferator-activated receptor gamma (PPARgamma [PPARG gene]). Rosiglitazone (RSG), a PPARgamma agonist, improves congenital lipoatrophy but not HIV lipoatrophy.


METHODS
Serial fat biopsies were taken from HIV-infected, lipoatrophic men randomized to receive RSG or placebo for 48 weeks. Adipose tissue mitochondrial and nuclear gene expression and mitochondrial DNA content were quantified by real-time polymerase chain reaction. Nonparametric analyses were applied.


RESULTS
Subjects receiving tNRTI-containing antiretroviral therapy had lower baseline mitochondrial RNA expression and DNA content. In subjects receiving tNRTIs, exposure to RSG did not affect PPARG expression at either week 2 or 48. At week 2, RSG increased PPARG expression only in subjects not treated with tNRTIs, whereas at week 48, increased PPARG expression was observed in subjects not treated with tNRTIs, regardless of RSG use. Similar findings were observed for the PPARG-responsive gene fatty acid-binding protein 4. Changes in PPARG expression were associated with increases in limb fat mass.


CONCLUSIONS
These data suggest that in HIV-infected, lipoatrophic men, adipose PPARG expression and function are dependent on intact mitochondrial function. These data support a direct link between mitochondrial toxicity and adipose tissue PPARG expression and help explain the poor clinical response to RSG observed in clinical trials.
Mallon
Patrick W G
PW
National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Australia. paddy.mallon@ucd.ie
Sedwell
Rebecca
R
Rogers
Gary
G
Nolan
David
D
Unemori
Patrick
P
Hoy
Jennifer
J
Samaras
Katherine
K
Kelleher
Anthony
A
Emery
Sean
S
Cooper
David A
DA
Carr
Andrew
A
D000273:Adipose Tissue / Q000378:metabolism*; D000328:Adult; D019380:Anti-HIV Agents / Q000009:adverse effects*; D001823:Body Composition / Q000187:drug effects; D004272:DNA, Mitochondrial / Q000378:metabolism; D004334:Drug Administration Schedule; D050556:Fatty Acid-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D039682:HIV-Associated Lipodystrophy Syndrome / Q000188:drug therapy / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D008928:Mitochondria / Q000187:drug effects*; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012313:RNA / Q000235:genetics / Q000378:metabolism; D000077278:RNA, Mitochondrial; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D019380:Anti-HIV Agents; D004272:DNA, Mitochondrial; C493410:FABP4 protein, human; D050556:Fatty Acid-Binding Proteins; D006360:Heat-Shock Proteins; D007004:Hypoglycemic Agents; D047495:PPAR gamma; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D000077278:RNA, Mitochondrial; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone; D012313:RNA